Personalized medicine for breast oncology is in evolution. Currently, oncologists use prior clinical trials data to recommend multiple therapies based upon features of the tumor and clinical stage of the patient. A limitation with this approach is that these data are averaged from large groups of patients that are then applied to each individual. This creates uncertainty as there is currently no reliable method to identify individua patients who truly have microscopic residual disease after primary therapy from those that are already cured. Thus, oncologists tend to treat the majority of patients with multiple therapies knowing from past clinical trials that most patients do not need these additional therapies, resulting in overtreatment. This project proposes an alternative model that will lead to a paradigm shift in how oncologists recommend and follow responses to therapy. The research team proposes that using the newer technologies of droplet digital PCR (ddPCR) and next generation sequencing (NGS), plasma tumor DNA (ptDNA) molecules shed into the circulation from cancer cells can be reliably detected and measured. They have already demonstrated the ability to detect microscopic residual disease using these technologies in early stage breast cancer patients. The team proposes a transforming project to address specific unmet needs in early stage (curative intent) breast cancer. It is well known that there are subsets of breast cancer patients who upon completion of preoperative chemotherapy (neoadjuvant therapy; NAT) have no evidence of cancer in the breast and lymph nodes. This is termed a pathologic complete response (pCR), and is associated with a favorable prognosis. This raises the question of whether these patients need surgery after NAT, however, patients must undergo surgery to know that they have achieved a pCR. The team will solve this conundrum by determining if the absence of detectable ptDNA after NAT will predict for a pCR and they will therefore define a liquid pCR. Based on their data, the team hypothesizes that >95% of patients without detectable ptDNA after NAT will have a pCR. This will set the stage for future studies to determine if patients without detectable ptDNA after NAT can safely forego surgery and/or radiation therapy, similar to the paradigm shift in treating anal cancer decades ago. A second long-term goal of this work is to determine in future studies whether the presence of ptDNA after NAT identifies a subset of patients with significant risk for future recurrence, which could therefore serve as a platform for clinical trials with new targeted therapies for patients wih detectable ptDNA. Ultimately measuring ptDNA will enable individual therapy options and change the current practice of overtreatment in early stage disease.